No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Thermoresponsive Formation of Dimethyl Cyclodextrin Polypseudorotaxanes and Subsequent One-Pot Synthesis of Polyrotaxanes
Abstract
We demonstrated a new strategy for efficient preparation of polypseudorotaxanes (PpRXs) and polyrotaxanes (PRXs) with cyclodextrin derivatives, 2,6-di-O-methyl-cyclodextrins (DM-CyDs), by utilizing the cloud points of DM-CyDs. DM-α-CyD and DM-β-CyD formed PpRXs with polyethylene glycol (PEG) and polypropylene glycol (PPG) in water at >50 °C and >35 °C, respectively, but did not at room temperature. Meanwhile, randomly methylated β-CyD (RM-β-CyD) and 2,3,6-tri-O-methyl-β-CyD (TM-β-CyD) did not form PpRX with PPG at higher temperature. The driving force of thermoresponsive formation of DM-CyD PpRXs was derived from hydrophobic interaction of methyl groups and a hydrogen bond of hydroxyl groups formed by adjacent DM-CyD molecules. Furthermore, in one pot, DM-CyD PRXs were synthesized by capping the PpRXs with bulky ends in high yields.
... His group also prepared various water-soluble polyrotaxanes including HP-β-CyD and 4-sulfobutyl ether β-CyD (SBE-β-CyD) using the same method. 40) We recently demonstrated a novel strategy for the efficient preparation of polypseudorotaxanes and polyrotaxanes with 2,6-di-O-methyl α-CyD (DM-α-CyD) and DM-β-CyD by using the cloud points of DM-CyDs. 41) Both DM-α-CyD and DM-β-CyD easily formed polypseudorotaxanes in water at high temperature (Fig. 3). ...
... Notably, the polyrotaxane released HEE-β-CyD in the target cells through degradation of polyrotaxane in the acidic environment of the cells (Fig. 4). Thompson and co-workers 39,40,122,123) also developed polyrotaxanes comprising HP-β-CyD and used them for NPC treatment. These findings suggest the potential of CyD-based supermolecules as advanced APIs. ...
Supramolecular chemistry is an extremely useful and important domain for understanding pharmaceutical sciences because various physiological reactions and drug activities are based on supramolecular chemistry. However, it is not a major domain in the pharmaceutical field. In this review, we propose a new concept in pharmaceutical sciences termed “supramolecular pharmaceutical sciences,” which combines pharmaceutical sciences and supramolecular chemistry. This concept could be useful for developing new ideas, methods, hypotheses, strategies, materials, and mechanisms in pharmaceutical sciences. Herein, we focus on cyclodextrin (CyD)-based supermolecules, because CyDs have been used not only as pharmaceutical excipients or active pharmaceutical ingredients but also as components of supermolecules.
Graphical Abstract Fullsize Image
... Recently, various polymers that are grafted with PEG chains have attracted massive interest for their thermal behavior induced by PEG side chains [101]. While considering this behavior, Arima et al. [102] prepared thermo-responsive hydrogels from an α-cyclodextrin derivative (2,6-di-O-methyl-cyclodextrin) and polyethylene glycol or polypropylene glycol in water at temperatures of >50 or >35 • C, respectively, but they did not form at room temperature. Ogawa et al. [103] suggested that drugs could be incorporated into the intermolecular spaces of cyclodextrin crystalline columns in α-CD/PEG polypseudorotaxanes. ...
Supramolecular hydrogels that are based on inclusion complexes between α-cyclodextrin and (co)polymers have gained significant attention over the last decade. They are formed via dynamic noncovalent bonds, such as host–guest interactions and hydrogen bonds, between various building blocks. In contrast to typical chemical crosslinking (covalent linkages), supramolecular crosslinking is a type of physical interaction that is characterized by great flexibility and it can be used with ease to create a variety of “smart” hydrogels. Supramolecular hydrogels based on the self-assembly of polypseudorotaxanes formed by a polymer chain “guest” and α-cyclodextrin “host” are promising materials for a wide range of applications. α-cyclodextrin-based polypseudorotaxane hydrogels are an attractive platform for engineering novel functional materials due to their excellent biocompatibility, thixotropic nature, and reversible and stimuli-responsiveness properties. The aim of this review is to provide an overview of the current progress in the chemistry and methods of designing and creating α-cyclodextrin-based supramolecular polypseudorotaxane hydrogels. In the described systems, the guests are (co)polymer chains with various architectures or polymeric nanoparticles. The potential applications of such supramolecular hydrogels are also described.
... Mono-(6-azido-6-desoxy)-β-CD was selected as the stopper in this method. Taishi et al. synthesized polypseudorotaxanes and polyrotaxanes using CD derivatives, 2,6-di-O-methyl-CDs (DM-CyDs), at temperatures relatively higher than room temperature via a one-pot synthetic method [66]. DM-α-CyD and DM-β-CyD formed polypseudorotaxanes with PEG and polypropylene glycol in water at >50 C and > 35 C, respectively. ...
With the emergence of supramolecular chemistry and modern nanotechnology, a great deal of research has been conducted on idiosyncratic classes of molecular structures held together by non-covalent mechanical interactions. Examples include the catenanes, rotaxanes, and knots, which are termed mechanically interlocked molecules. Steadily but inevitably, mechanically interlinked architectures are beginning to effectuate their promise as components of molecular machines that display a number of outstanding performances. Moreover, the consolidation of chemical, biological, and physical sciences has unlocked multitudinous and versatile techniques to implement supramolecular structures into new hybrid materials and stimuli-responsive artificial machines at the molecular level, such as actuators, muscles, shuttles, motors, pumps, valves, switches, piston-cylinders, ratchets, elevators, and so on. The chapter “Polyrotaxane Actuators” is organized into four sections. In the first section, the definition, synthesis, and properties of rotaxanes and polyrotaxanes are given. The design, synthesis, applications, and modifications of polyrotaxane-based molecular machines are described in the second section. The third and fourth sections delineate the practical and effective uses of polyrotaxanes in the fabrication of soft materials and the future prospects of polyrotaxanes as actuators, respectively.
In the context of the continuous increase in global grain production, accompanied by a large amount of investment in various pesticides, herbicides, fungicides, and other chemical pesticides. It has caused inevitable environmental problems and food safety problems. Current research suggests that the use of cyclodextrins and their derivatives to protect pesticides can significantly reduce the number of agrochemicals that pollute the environment. Using the cavity properties of cyclodextrins, we can refer to the similar way in which drug molecules make cyclodextrins and cyclodextrin polymers to form inclusion compounds. Overall, β-cyclodextrin and its derivatives are used as a new pesticide excipient to improve the stability of pesticides, prevent their oxidation and decomposition, improve the solubility and bioavailability of pesticides, reduce the toxic side effects of drugs, and mask the odour of drugs. In this review, we focus on summarising the recent research progress of β-cyclodextrins and their derivatives in pesticides and other fields, and provide a systematic classification of β-cyclodextrin polymers, as well as new synthesis methods and techniques in various applications. Finally, the future development of cyclodextrin-like polymers is foreseen, and issues arising from the research are discussed and addressed in depth.
Polyrotaxanes (PRXs) containing acetylated α-cyclodextrins exhibit a temperature-dependent phase transition in aqueous solutions across their lower critical solution temperature (LCST) of approximately 26.6 °C. To gain insights into the interactions of acetylated PRXs (Ac-PRXs) with biological components, thermoresponsive supramolecular surfaces were prepared by coating tissue culture polystyrene (TCPS) surfaces with Ac-PRX triblock copolymers, and their surface properties across the LCST were evaluated. The wettability and protein adsorption of Ac-PRX-coated surfaces changed significantly between 10 and 37 °C, whereas the uncoated TCPS and unmodified PRX-coated surfaces did not alter the wettability and protein adsorption at 10 and 37 °C. The adhesion, proliferation, morphology, and adhesion strength of NIH/3T3 cells on Ac-PRX-coated surfaces were found to be similar to those of the uncoated and unmodified PRX-coated surfaces. However, the adhesion strength of NIH/3T3 cells on Ac-PRX-coated surfaces decreased drastically at 10 °C. Consequently, the cells spontaneously detached from the Ac-PRX-coated surfaces without enzymatic treatment. Additionally, when incubating confluent cells at 10 °C, the cells detached from Ac-PRX-coated surfaces as cell sheets while retaining extracellular matrix proteins. The findings of this study provide new directions for the design of thermoresponsive supramolecular biointerfaces for applications in bioseparation and cell manipulation.
As an effective alternative to suture in wound closure, tissue adhesives often need to have excellent biocompatibility and suitable bioadhesion. To achieve long‐term adhesion on moist tissue, polyrotaxane (PR) crosslinked self‐healing hydrogels have been prepared by the introduction of dynamic borate bonds between PR bearing phenylboronic acid moieties (PR‐PBA) and dopamine grafted poly(vinyl alcohol) (PVA‐DOP). Synthesis of these precursor polymers PR‐PBA and PVA‐DOP is quite simple and the hydrogels combine dynamic borate bonds with the sliding motion of the phenylboronic acid moieties on PR. The sliding nature of the crosslinking points along the axle in the PR is thought to enhance the mechanical properties and adhesion ability of the resultant hydrogels. Meanwhile, catechol groups on dopamine units have been protected by borate bonds under alkaline conditions to avoid oxidation, and they then are released to react with various functional groups on tissue surface to ensure the switchable tissue adhesion. The self‐healing test and adhesion of hydrogels on pigskin demonstrate the ability to restore the original performance after repeated strain cycles and maintain strong tissue adhesion. The components of these hydrogels have satisfying biocompatibility. These results indicate that these self‐healing hydrogels have great potentials in tissue adhesion.
Stimuli‐responsive materials have received considerable attention for their application in biomedical fields. Herein, the temperature‐dependent phase transition behavior of acetylated polyrotaxanes (Ac‐PRXs) consisting of acetylated cyclodextrins threaded onto a linear axle polymer in aqueous solution is investigated. The aqueous solutions of Ac‐PRXs exhibit temperature‐dependent transmittance changes when the degree of acetylation is 30–40%. Upon increasing the temperature, Ac‐PRXs are dehydrated and acetyl groups are subsequently associated through hydrophobic interactions. Interestingly, the Ac‐PRXs form coacervate droplets with a diameter of ≈2–3 µm above their cloud points. These temperature‐responsivities of Ac‐PRXs are observed for other PRXs with different axle polymer molecular weights and compositions. Consequently, the acetylation of PRXs is an attractive chemical modification for yielding temperature‐responsivities, and Ac‐PRXs can be applied as temperature‐responsive supramolecular materials.
Thermo-responsive 3D-printed hydrogels that are composed of methylated α-cyclodextrin polyrotaxanes have been synthesized through post-3D-printing methylation. With a high methylation degree of the threaded α-cyclodextrins, the fabricated monolith exhibits a two-stage thermo-induced aggregation behavior, in which a second micro-crystallization process was identified for the first time. The methylated polyrotaxane monoliths possess reversible temperature-dependent size, transparency, and elastic moduli switching in an aqueous environment. Through dual-material 3D printing, the 3D-printed monolith actuates back-and-forth at different temperatures.
OEGylated cyclodextrin-threaded polyrotaxanes (PRXs) capped with UV-cleavable stoppers were synthesized, and their thermoresponsive and degradable behavior were investigated. These PRXs in aqueous solutions exhibit fast thermally induced phase transitions and small hysteresis as well as tunable phase transition temperatures, which are quite distinct from previous methylated PRXs. Based on the mechanically interlocked architecture, PRXs are stable in solutions but can be completely degraded into hydrophilic components upon UV cleavage of stoppers. As a consequence, the thermoresponsive behavior of PRXs was switched off. Furthermore, micrometer-scale globular aggregates were formed from thermoresponsive PRXs above their phase transition temperatures but disaggregated quickly upon cooling or UV irradiation. This phenomenon was utilized to take these PRXs as unique carriers for guests with dually controlled release by both temperature and light. The present work provides efficient synthesis of a new class of thermoresponsive interlocked polymers with on-demand degradation, and the findings illustrate the prominent effect of PRX architecture on the remarkable thermoresponsive and degradable behavior.
Recently, active pharmaceutical ingredients (APIs) have been dramatically expanding from low-molecular weight drugs to peptides, proteins, antibodies, genes, oligonucleotides, cells, and machines. Therefore to develop pharmaceutical technologies and drug delivery systems (DDS) for these APIs, advanced molecules and novel concepts are needed. In this review, we introduce cyclodextrin-based supramolecular accessories such as molecular necklace, molecular earring, and intelligent molecular necklace, and describe their application for pharmaceutical technology and DDS. In addition, we also introduce utility of supramolecular accessories as antitumor drugs. Finally, we propose a new concept in pharmaceutical sciences termed as “supramolecular pharmaceutical sciences,” which combines pharmaceutical sciences and supramolecular chemistry. This concept could be useful for developing new ideas, methods, hypotheses, strategies, materials, and mechanisms in pharmaceutical sciences.
Graphical Abstract Fullsize Image
Recently, the application of β-cyclodextrins (β-CDs) as therapeutic agents has received considerable attention. β-CDs have been reported to have therapeutic effects on various diseases, such as Niemann-Pick type C (NPC) disease, a family of lysosomal storage disorders characterized by the lysosomal accumulation of cholesterol. To further improve the therapeutic efficacy of β-CDs, the use of β-CD-threaded polyrotaxanes (PRXs) has been proposed as a carrier of β-CDs for NPC disease. PRXs are supramolecular polymers composed of many CDs threaded onto a linear polymer chain and capped with bulky stopper molecules. In this review, the design of PRXs and their therapeutic applications are described. To achieve the intracellular release of threaded β-CDs from PRXs, stimuli-cleavable linkers are introduced in an axle polymer of PRXs. The stimuli-labile PRXs can dissociate into their constituent molecules by a cleavage reaction under specific stimuli, such as pH reduction in lysosomes. The release of the threaded β-CDs from acid-labile PRXs in acidic lysosomes leads to the formation of an inclusion complex with the cholesterol that has accumulated in NPC disease patient-derived fibroblasts, thus promoting the extracellular excretion of the excess cholesterol. Moreover, the administration of PRXs to a mouse model of NPC disease caused significant suppression of the tissue accumulation of cholesterol, resulting in a prolonged life span in the model mice. Additionally, the induction of autophagy by the methylated β-CD-threaded PRXs (Me-PRXs) is described. Accordingly, the stimuli-labile PRXs are expected to be effective carriers of CDs for therapeutic applications.
Supramolecular chemistry is a useful and important domain for understanding pharmaceutical sciences, since various physiological reactions (e.g., protein association) and drug activities (e.g., the substrate/receptor reaction) are based on supramolecular chemistry. Biological components, such as DNA and cells, are also supermolecules. However, supramolecular chemistry to date has not been a major domain in the field of pharmaceutical study. In this article, we propose a new concept in pharmaceutical sciences termed “supramolecular pharmaceutical sciences” which combines pharmaceutical sciences and supramolecular chemistry. “Supramolecular pharmaceutical sciences” could encompass strictly controlled molecular arrangement, stimulus responsible molecular motion, new functions beyond those of existing molecules, more accurate drug design, new active pharmaceutical ingredients, new perspectives for the investigation of the drug mechanisms, and novel pharmaceutical technologies. Moreover, pharmaceutical sciences are useful for supramolecular chemistry, because biological reactions are very accurate reactions, making this a win-win relationship. Thus, supramolecular pharmaceutical sciences could be useful for developing new methods, hypotheses, ideas, materials, mechanisms, and strategies in the realm of pharmaceutical science.
In prior research, it has been demonstrated that methylated β-cyclodextrins-threaded acid-labile polyrotaxanes (Me-PRXs) exhibit a lower critical solution temperature (LCST) and form coacervate droplets above their LCST. In this study, the encapsulation of proteins in coacervate droplets and the pH-responsive release of proteins, through the acid-induced dissociation of the Me-PRX, were investigated. The coacervate droplets encapsulate various proteins, such as bovine serum albumin (BSA), lysozyme, and β-galactosidase, at pH 7.4, into their hydrophobic inner phase. Concomitant with the pH-dependent dissociation of the Me-PRXs, the coacervates degraded below pH 6.5 and released encapsulated proteins, with the intrinsic activity of proteins maintained. Additionally, the subcutaneous injection of coacervate droplets encapsulating BSA in mice revealed that the retention time of the BSA at the injection site was prolonged compared to that of free BSA. Altogether, the coacervate droplets of the Me-PRX would be utilized as a new class ofpH-responsive and injectable carrier for the controlled release of therapeutic proteins.
Ternary hydrogels composed of poly[acrylamide-co-2-(dimethylamino)ethyl methacrylate] [P(AM-co-DMAEMA)], poly(vinyl alcohol) (PVA) and β-cyclodextrin (β-CD) were fabricated based on the multiple physical interactions such as inclusion complexation, hydrogen bonding and polymer crystallinity, and exhibited high storage modulus. To illustrate the individual role of each physical interaction, symmetrical investigation has been performed. P(AM-co-DMAEMA)s with two compositions, prepared by radical polymerization at −20 °C below the freezing point of reaction medium of water, were served as the inclusion guest for the inclusion host of β-CD. The inclusion complex between dimethylaminoethyl group of DMAEMA and β-CD was identified through 2D NOESY NMR spectroscopy. Hydrogen bonding between each pairs of hydrogel components was confirmed with FTIR analysis and contributed the second form of crosslinkage. Under freezing polymerization and further freezing-thawing treatment, PVA component tended to crystallize to serve as the third type of physical crosslinkage, which was recognized with X-ray diffraction. Rheological and thermo-gravimetrical analysis was used to inspect the modulus and thermal stability of the hydrogels, respectively. Three hydrogels of P(AM-co-DMAEMA)/PVA-g-β-CD, P(AM-co-DMAEMA)/PVA/β-CD and P(AM-co-DMAEMA)/PVA were synthesized under the same condition to make the comparison. The whole results disclosed the strong dependence of hydrogel properties on the hydrogel components, reflecting the synergistic effects of different physical crosslinkages for the formation of those physical hydrogels.
Chemotherapy is facing several limitations such as low water solubility of anticancer drugs and multidrug resistance (MDR) in cancer cells. To overcome these limitations, a thermoresponsive micellar drug delivery system formed by a non-covalently connected supramolecular block polymer was developed. The system is based on the host-guest interaction between a well-defined β-cyclodextrin (β-CD) based poly(N-isopropylacrylamide) star host polymer and an adamantyl-containing poly(ethylene glycol) (Ad-PEG) guest polymer. The structures of the host and guest polymers were characterized by ¹H and ¹³C NMR, GPC and FTIR. Subsequently, they formed a pseudo-block copolymer via inclusion complexation between β-CD core and adamantyl-moiety, which was confirmed by 2D NMR. The thermoresponsive micellization of the copolymer was investigated by UV-vis spectroscopy, DLS and TEM. At 37 °C, the copolymer at a concentration of 0.2 mg/mL in PBS formed micelles with a hydrodynamic diameter of ca. 282 nm. The anticancer drug, doxorubicin (DOX), was successfully loaded into the core of the micelles with a loading level of 6% and loading efficiency of 17%. The blank polymer micelles showed good biocompatibility in cell cytotoxicity studies. Moreover, the DOX-loaded micelles demonstrated superior therapeutic effects in AT3B-1-N (MDR-) and AT3B-1 (MDR+) cell lines as compared to free DOX control, overcoming MDR in cancer cells.
Paclitaxel (PTX), a hydrophobic anticancer drug, is facing several clinical limitations such as low bioavailability and drug resistance. To solve the problems, a well-defined b-cyclodextrin-poly(N-isopropylacrylamide) star polymer was synthesized and used as a nanocarrier to improve the water solubility and aim to thermoresponsive delivery of PTX to cancer cells. The star polymer was able to form supramolecular self-assembled inclusion complex with PTX via host-guest interaction at room temperature, which is below the low critical solution temperature (LCST) of the star polymer, significantly improving the solubilization of PTX. At body temperature (above LCST), the phase transition of poly(N-isopropylacrylamide) segments induced formation of nanoparticles, which greatly enhanced the cellular uptake of the polymer-drug complex, resulting in efficient thermoresponsive delivery of PTX. Particularly, the polymer-drug complex exhibited better antitumor effects than the commercial formulation of PTX in overcoming the multidrug resistance in AT3B-1 cells.
Polyrotaxanes (PRXs) composed of threading methylated cyclodextrins exhibit a temperature-dependent reversible phase transition across the lower critical solution temperature (LCST) in water. In this study, a variety of methylated β-cyclodextrin (β-CD)-threaded PRXs (Me-PRXs) with different number of methyl groups modified on the β-CD and with different compositions of axle polymers (i.e., Pluronic, PEG-b-PPG-b-PEG) were synthesized, and the relationship between the LCST value and structural parameters was investigated. The LCST values of the Me-PRXs decreased with an increasing the methylation degree of the threading β-CD. Differential scanning calorimetric measurements demonstrated that the temperature-induced phase transition of the Me-PRXs occurred due to the dehydration of the threading methylated β-CD moieties and the subsequent hydrophobic interactions. Interestingly, the Me-PRXs formed coacervate droplets above their LCST. Altogether, we concluded that the LCST values of the Me-PRXs varied according to their structural parameters and could be applied as temperature-responsive biomaterials or therapeutics.
A molecular necklace of polypseudorotaxanes was prepared by threading β-cyclodextrins (β-CD) onto biodegradable and thermoresponsive polyurethanes derived from bile acids. These polyurethanes were synthesized via a simple step condensation of bile acid-based dicarbonate with poly(ethylene glycol)-diamine. The β-CD rings slide onto the poly(ethylene glycol) segments and selectively recognize the bile acid units of the polyurethane chains, whereas the poly(ethylene glycol) segments remain crystalline with a lower crystallinity. This bio-compound-derived molecular necklace can be visualized by scanning tunneling microscopy. The polypseudorotaxanes show thermosensitivity in water and the phase transition temperature may be fine-tuned by varying the molar ratios of β-CD to the bile acid units. Such an interesting necklace model of polypseudorotaxane constructed from natural compounds may lead to the further exploration of their applications, such as as an enzyme model, due to their biological nature.
A molecular necklace of polypseudorotaxanes was prepared by threading β-cyclodextrins (β-CD) onto biodegradable and thermoresponsive polyurethanes derived from bile acids. These polyurethanes were synthesized via a simple step condensation of bile acid-based dicarbonate with poly(ethylene glycol)-diamine. The β-CD rings slide onto the poly(ethylene glycol) segments and selectively recognize the bile acid units of the polyurethane chains, whereas the poly(ethylene glycol) segments remain crystalline with a lower crystallinity. This bio-compound-derived molecular necklace can be visualized by scanning tunneling microscopy. The polypseudorotaxanes show thermosensitivity in water and the phase transition temperature may be fine-tuned by varying the molar ratios of β-CD to the bile acid units. Such an interesting necklace model of polypseudorotaxane constructed from natural compounds may lead to the further exploration of their applications, such as as an enzyme model, due to their biological nature.
Cyclodextrins (CyDs) include linear polymers such as polyethylene glycol (PEG), polypropylene glycol (PPG) and polyethyleneimine (PEI) and spontaneously form supramolecular inclusion complexes, namely polypseudorotaxanes. When both ends of the polymer chains in polypseudorotaxanes are covalently capped with bulky molecules, CyDs are trapped in and cannot be dethreaded from the assembly, giving the so-called polyrotaxane. Recently, a large number of drug carriers based on polyrotaxanes and polypseudorotaxanes have been developed for various drugs, i.e., low molecular weight drugs, protein drugs, gene drugs and nucleic acid drugs. In this review, we introduce various applications of polyrotaxanes and polypseudorotaxanes as drug delivery techniques such as drug absorption, controlled release and drug targeting for various drugs.
The polymer surfaces with a wide range of hydrated surface mobility are developed by a simple deposition method with supramolecular block copolymers. The morphologies of adhering stem cells are greatly dependent on the surface mobility of polymers, and this induces significant changes in the cytoskeletal signaling pathway to direct the downstream stem cell differentiation.
Hexakis(2,6-di-O-methyl)-α-cyclodextrin (DMαCD) crystallizes in the space group P21 from 10% NaCl aqueous solution at room temperature and in the space group P212121 by the slow evaporation of water at ca. 90 °C. The P21 crystal shows a typical cage-type packing structure and a water molecule is included within its macrocyclic cavity. In the P212121 crystal, DMαCD molecules are arranged in a helically extended polymeric chain formed by the inclusion of an O-6CH3 methoxyl group of the adjacent molecule related by the twofold screw axis. In spite of the difference in the packing structure, the macrocyclic conformation of DMαCD molecules in the two crystals is nearly identical. The round structure of the macrocycle is maintained by the intramolecular O-3H—O-2 hydrogen bonds formed between adjacent residues. The rootmean-square distance between equivalent two atoms calculated after the least-squares superposition of the two molecules is 0.36 Å for non-hydrogen atoms except O-6 and methyl carbon atoms.
Five polyrotaxanes were synthesized by threading 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) onto a variety of α,ω-ditriethylenediamino-N-carbamoyl-poly-(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (Pluronic) triblock copolymers using a two-pot strategy under heterogeneous, nonaqueous conditions. The threaded HP-β-CD units were retained on the pseudopolyrotaxane precursors by end-capping the branched diamine termini with sodium 2,4,6-trinitrobenzene sulfonate. Inclusion of the Pluronic copolymers within the HP-β-CD cavities was more favorable in nonpolar solvents, such as diethyl ether and n-hexane, both of which gave better coverage ratios than polar solvents. (1)H NMR and MALDI-TOF were used to estimate the average molecular weights of the purified polyrotaxane products. A globular morphology of aggregated polyrotaxanes was observed by tapping-mode AFM imaging of dried samples. Treatment of Niemann-Pick C (NPC) type 2-deficient fibroblasts with the polyrotaxane derivatives produced substantial reductions in sterol accumulation, as seen by diminished filipin staining in these cells, suggesting that Pluronic-based polyrotaxanes may be promising vehicles for delivery of HP-β-CD to cells with abnormal cholesterol accumulation.
Efficient one-pot synthesis in water of polyrotaxanes, with native and permethylated alpha-cyclodextrins (alpha-CD and PMe alpha-CD) as the wheel components, is described. The procedure involves initial mixing of alpha-CDs and an amine-terminated linear polymer, which acts as the axle, by sonication and subsequent addition of ail end-capping agent for the axle terminal amino groups. The polyrotaxanes were prepared by mixing the axle and wheel components by sonication for 30 min at room temperature and standing overnight if necessary, followed by treatment with a bulky isocyanate in water at 0 degrees C for an hour. Both amine-terminated polytetrahydrofuran (ATPT) and poly(ethylene glycol) (ATPEG) afforded the corresponding polyrotaxanes (PRXs) in good yields (27-49%) in the case of a native alpha-CD wheel. The coverage ratio of the axle component with the wheel component of the PRXs ranged from 85% to 96% when the molecular weight of the axle was M(n) 1000-1800, while it was 54% when the axle was long (M(n) 7700). The polyrotaxanes (PMePRXs) with PMe alpha-CD and ATPT were similarly obtained in high yields. In this case, the yield of the PMePRXs was unusually high (66 and 69%) when a higher molecular weight axle (M(n) 4100 and 7100, respectively) was used. The formation of a PMePRX from ATPEG axle proceeded with low efficiency. The present work provides the first synthesis of polyrotaxanes with PMe alpha-CD in solution.
Methylated cyclodextrins were investigated to shed light on their solubility behavior in water where they exhibit a negative temperature coefficient, contrasting the positive temperature coefficient of unmodified cyclodextrins. Both heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DIMEB) and heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin (TRIMEB) show two different conditions of crystallization. At low temperatures around IS degreesC, highly hydrated clathrates are formed, whereas, at high temperatures around 60-70 degreesC, DIMEB crystallizes as an anhydrate and TRIMEB as a monohydrate. The crystallization at high temperature is driven by entropy gain of water to compensate for the positive enthalpy change associated with this crystallization process, as could be shown by differential scanning calorimetry experiments in H2O and D2O.
An X-ray diffraction study was carried out on dimethyl-β-cyclodextrin which crystallized from aqueous solution at 60°C without water of hydration. The molecule adopts a round shape which is stabilized by systematic intramolecular O-3H ż O-2 hydrogen bonds between neighboring glucose units. The O-6C-8 groups of three glucoses are oriented towards the molecular axis so that the cyclodextrin cavity is closed at one end. The remaining volume of the bowl-shaped cavity is occupied by part of the C-6O-6C-8 rim of a neighboring molecule (self-inclusion).
Binding properties of poly(tetrahydrofuran) (PTHF) to methylated cyclodextrins (CDs) in aqueous solutions were studied by turbidity titration and 1H NMR measurements. PTHF, which has a low solubility in water, was dissolved in water on addition of 2,6-di-O-methyl-β-CD (DM-β-CD) and DM-α-CD. 2,3,6-tri-O-methyl-β-CD (TM-β-CD) and TM-α-CD did not solubilize PTHF. When PTHF was mixed with aqueous solutions of DM-β-CD and TM-β-CD, the inclusion complexes crystallized after several days. 1,4-Butanediol (monomer model) and PTHF (Mw = 250) did not form crystalline complexes with methylated CDs. The yields of the complexes of PTHF with methylated β-CDs increased with increasing molecular weight of PTHF and reached a maximum at about Mw = 1000. The complexes were characterized by 1H NMR, solid-state 13C NMR, powder X-ray, and FT-IR measurements.
We achieved a highly efficient one-pot synthesis of permethylated α-cyclodextrin(CD)-based polyrotaxane via an initial complexation to the inclusion complex with amine-terminated polytetrahydrofuran followed by end-capping with a bulky isocyanate in hydrocarbon solvent under heterogeneous conditions. Among various organic solvents tested, isooctane was the best solvent, while cyclohexane yielded no polyrotaxane. Effects of the reaction temperature, the molecular weight of the axle polymer, the structures of the wheel and axle components on the yield and coverage ratio of the polyrotaxane were studied in detail. Under the optimum conditions, we obtained a 71% yield of polyrotaxane with a 67% coverage ratio when amine-terminated poly(tetrahydrofuran) (Mn 8700) reacted with permethylated α-cyclodextrin at 50 °C in isooctane. We discuss the reason for and the mechanism of the efficient reaction that occurred in the heterogeneous system from the viewpoint of the role of the solvent and the results of the solvent-free synthesis previously reported. By a similar one-pot reaction, polyrotaxane consisting of permethylated α-cyclodextrin and poly(ethylene glycol) was first synthesized. Neither native α-CD nor permethylated β-CD gave any polyrotaxanes when amine-terminated poly(tetrahydrofuran) was used as an axle polymer.
Alpha-cyclodextrin (alpha-CD) was found to form inclusion complexes with poly(ethylene glycol) (PEG) of various molecular weights to give stoichiometric compounds in a crystalline state in high yields. Alpha-CD does not form complexes with the low molecular weight analogs, ethylene glycol, diethylene glycol, and triethylene glycol. The rate of the complex formation depends on the molecular weight of PEG. PEG of molecular weight 1000 forms complexes most rapidly. The complexes were characterized by IR, H-1 NMR, C-13 NMR, and C-13 CP/MAS NMR spectra and X-ray (powder), thermal, and elemental analyses. The H-1 NMR spectra of the complexes show that the stoichiometry of the complexes is 2:1 (two ethylene glycol units and one alpha-CD). X-ray powder patterns of the PEG-alpha-CD complex show that alpha-CDs form channels. The C-13 CP/MAS NMR spectrum of the complex suggests that a PEG chain is included in the channel formed by alpha-CDs. Alpha-CD formed complexes with PEG having small end groups, such as methyl, dimethyl, and amino groups, but did not form complexes with PEG carrying large substituents, such as 2,4-dinitrophenyl and 3,5-dinitrobenzoyl groups. beta-CD did not form complexes with poly(ethylene glycol) of any molecular weight. The modes of the complexes are discussed.
Aqueous solutions of α-cyclodextrin (α-CD) and polyethylene glycol (PEG) form interesting complexes, where several α-CD units are penetrated by the linear polymeric PEG chain and produce a so-called “polyrotaxane”. This supramolecular structure is stabilized by strong interactions between the α-CD hydrophobic internal cavity and the −CH2OCH2− moieties of PEG. When cyclodextrins have occupied the whole PEG chain, the polyrotaxanes aggregate and precipitate, forming a thick solid gel. Turbidity measurements at λ = 400 nm were used to study the threading phenomenon. The temperature of the solution and the composition of the solvent affect the formation of polyrotaxanes in a significant way. We propose a molecular model to explain the experimental findings in terms of a multistep threading process. The Gibbs free energy related to the formation of polyrotaxanes is calculated according to the transition state theory.
The complex formation between methylated cyclodextrins (CDs) and poly(propylene glycol) (PPG) in water is described. PPG diamine (Mw = 4000) (PPGN4000) was solubilized in the water phase in the presence of 2,6-O-dimethyl-β-CD (DM-β-CD). 2,3,6-Trimethyl-O-α-CD (TM-α-CD), DM-α-CD, and TM-β-CD did not solubilize PPGN and did not give any precipitated complexes. The effects of DM-β-CD on the solubility of PPG were dependent on the Mw of PPG. The interactions between DM-β-CD and PPG were studied by NMR relaxation spectroscopy in D2O. The 1H resonance of C(3)H at the inner wall of DM-β-CD shifted upfield on addition of PPG. The 1H spin−lattice relaxation times of C(3)H and C(5)H of DM-β-CD markedly increased on addition of PPG. These results show that a PPG chain is included in the cavities of DM-β-CD in an aqueous solution. When PPGN4000 was vigorously stirred with a saturated aqueous solution over 2 days, the mixture became turbid to give precipitated complexes. The DM-β-CD−PPGN4000 complexes were characterized by 1H NMR, solid-state 13C NMR, powder X-ray diffraction, atomic force microscopy, and FT-IR techniques. The complex formation between DM-β-CD and PPG was found to consist of two processes: the solubilization of PPG and the precipitation of complexes. The complexation phenomena between poly(ethylene glycol) (PEG) and methylated CDs were also studied in a similar manner. The interaction of PEG with DM-β-CD is much weaker than that of PPG.
A smart material design of cationic supramolecular polyrotaxane entities for efficient gene delivery was investigated. Oligoethylenimine-grafted β-CD was selected as the building block because β-CD is larger than Α-CD and can accommodate grafting. For blocking the ends of the copolymers to prevent the dethreading of β-CD a bifunctional end group was designed. To assure that there was no intra- or intermolecular crosslinking a large excess of OEI was used in the grafting reactions. The ability of the cationic polyrotaxanes to condense plasmid DNA (pDNA) into particular structures was confirmed by agarose gel electrophoresis. The4 transfection efficiency of cationic-polyrotaxane-DNA complexes was assessed using luciferase as marker gene. It was observed that the use of dimethylaminoethyl-modified Α-CD threaded onto a PEO chain and capped by cleavable end groups and the system has a lot of flapping OEI chains with many primary and secondary amines.
Various polyrotaxane modification reactions, such as methylation, hydroxy propylation, tritylation, acetylation, trimethylsilylation, phenylcarbamation, dansylation, and nitration, were examined to obtain polyrotaxane derivatives, in which various functional groups were attached to cyclodextrin moieties. Although the nitrate could not be obtained because of significant degradation of the polyrotaxane under the conditions examined, other derivatives were successfully prepared under moderate conditions. The introduction of these functional groups and their degree of substitution were assessed with Fourier transform infrared and NMR spectroscopy. The polyrotaxane derivatives thus obtained were soluble in various organic solvents other than the conventional solvents (dimethyl sulfoxide and aqueous NaOH) used for the unmodified polyrotaxane. That is, the solubility of the polyrotaxane was drastically changed by the examined modification reactions. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 6312–6323, 2006
X-ray diffraction studies were carried out on hexakis-(2,6-di-O-methyl)-cyclomaltohexaose (dimethyl-α-cyclodextrin, DIMEA) crystallized at room temperature from solutions in pure acetone as the 1:1 inclusion complex, and crystallized from aqueous solution at 80 °C without water of hydration. In both crystal structures, the DIMEA molecules adopt a round shape stabilized by systematic intramolecular O-3H … O-2 hydrogen bonds between neighbouring glucose units, and the DIMEA-cavities are closed at the O-6Me rims by methoxy groups forming van der Waals contacts across the molecular opening. In the DIMEA-acetone complex, the guest molecule is fully included and exhibits excessive thermal motions. In anhydrous DIMEA, the remaining cavity volume is occupied by a methoxy group of a neighbouring DIMEA molecule.
Spectroscopic measurements (uv/vis absorbance and fluorescence) and time-resolved small-angle neutron scattering experiments (TR-SANS) were used to follow the breakdown of Pluronic micelles by heptakis(2,6-di-O-methyl)-β-cyclodextrin (DIMEB) over time in order to elucidate the mechanism of micellar rupture, generally attributed to polypseudotorotaxane (PR) formation between the cyclodextrin and the central hydrophobic PPO block. The spectroscopic measurements with two different probes (methyl orange and nile red) suggest that very rapid changes (on the order of seconds) take place when mixing DIMEB with F127 Pluronic and that no displacement of the probe from the cyclodextrin cavity occurs, which is in disagreement with PR formation. TR-SANS measurements demonstrate for the first time that the micelles are broken down in less than 100 ms, which categorically rules out PR formation as the mechanism of rupture. In addition, the same mechanism is demonstrated with other Pluronics, P85 and P123. In the latter case, after micellar rupture, lamellar structures are seen to form over a longer period of time, thus suggesting that after the instantaneous micellar disruption, further, longer-scale rearrangements are not excluded.
Various types of polyrotaxanes were studied according to their structures and components. Main chain polyrotaxane with cyclodextrin (CDs) are a family of macrocyclic oligosaccharides, the most common of which are composed of 6 (α), 7 (β), or 8 (γ) α-1,4-linked D-glucopyranose units. Construction of polyrotaxanes using CDs can be categorized in three types, the threading approach, slipping approach, and inclusion polymerization approach. The major driving forces for forming CD inclusion complexes are hydrophobic and van der Waals interactions between the inner surface of the CD ring and the hydrophobic sites of the guests. Metal ions play an important role to expand the rotaxane structures into the higher-ordered polyrotaxane frameworks. One class of polymeric rotaxanes consists of side chain polyrotaxanes and polypseudorotaxanes. Side chain polyrotaxanes and polypseudorotaxanes are categorized into the three systems, rotor/polyaxis systems, polyrotor/axis systems, and polyrotor/polyaxis systems.
Cyclodextrins (CDs) are 1 → 4 α-linked cyclic oligomers of anhydroglucopyranose. CDs consist of six, seven, or eight glucose entities and are called α-, β-, or γ-CDs respectively. CDs spontaneously incorporate guest molecules, a necessary prerequisite for rotaxane formation. This review covers both synthesis and properties of CD rotaxanes and pseudorotaxanes as published over the last seven years. Topics discussed include axial cyclodextrin inclusion compounds, synthesis of CD [2]-rotaxanes and [3]-rotaxanes, functions of CD inclusion compounds and rotaxanes, daisy chains: rotaxanes from conjugates of CDs and axes, CD pseudopolyrotaxanes, synthesis of CD polyrotaxanes, rotaxanes from covalently linked CDs, and functions of and applications for CD (pseudo)-polyrotaxanes.
Thermoreversible gelation and microphase formation of aqueous solutions of a methylated polyrotaxane (MePR) were investigated by means of differential scanning microcalorimetry, rheometry, and X-ray diffractometry (XRD). The aqueous solutions of MePR show a lower critical solution temperature (LCST) and form an elastic gel with increasing temperature. The sol-gel transition of the MePR solutions was induced by formation and deformation of aggregates of methylated alpha-cyclodextrins (alpha-CDs) of polyrotaxane due to hydrophobic dehydration and hydration, respectively. The XRD investigation revealed localization and highly ordered arrangement of methylated alpha-CDs along the PEG chain in the gel. The arrangement of CDs was also reflected by the changes in elasticity and long relaxation behavior of the solution around the sol-gel transition. The quasiequilibrium shear modulus of MePR solutions showed the critical phenomena against temperature. The scaling exponents measured at two different concentrations were almost equal to the values predicted by a gel percolation theory. Therefore, the heat-induced gelation of aqueous MePR solutions is well explained by a model in which clusters assembled with methylated alpha-CDs are gradually connected to the network as the temperature increases.
Aqueous solutions of polyrotaxanes consisting of poly(ethylene glycol) and methylated alpha-cyclodextrins (alpha-CD) were studied by means of differential scanning calorimetry (DSC), dynamic light scattering, and X-ray diffraction in order to investigate the effect of the degree of methylation on thermoresponsive behavior. Polyrotaxanes with a degree of methylation higher than 50% had a lower critical solution temperature (LCST) and showed reversible associations and dissociations in water. In the transmittance measurements, the cloud point of methylated polyrotaxanes (MePR) shifted to a lower temperature with an increase in the degree of methylation. The heating curve obtained by DSC for the nearly permethylated polyrotaxane showed one broad endothermic peak that was associated with the microcrystallization of methylated CDs by hydrophobic interactions. On the other hand, the DSC profiles for partially methylated polyrotaxanes had several endothermic peaks, indicating multiple phase transitions of the MePR solutions. The results imply that the thermal properties of the MePR-water system are significantly affected by not only the methyl groups on alpha-CDs but also by the remaining hydroxyl groups.
The supramolecular structures formed between cyclodextrins (CDs) and polymers have inspired interesting developments of novel supramolecular biomaterials. This review will update the recent progress in studies on supramolecular structures based on CDs and block copolymers, followed by the design and synthesis of CD-based supramolecular hydrogels and biodegradable polyrotaxanes for potential controlled drug delivery, and CD-containing cationic polymers and cationic polyrotaxanes for gene delivery. Supramolecular hydrogels based on the self-assembly of the inclusion complexes between CDs with biodegradable block copolymers could be used as promising injectable drug delivery systems for sustained controlled release of macromolecular drugs. Biodegradable polyrotaxanes with drug-conjugated CDs threaded on a polymer chain with degradable end-caps could be interesting supramolecular prodrugs for controlled and targeting delivery of drugs. CD-containing cationic polymers as gene carriers showed reduced cytotoxicity than non-CD-containing polymer counterparts. More importantly, the polyplexes of CD-containing cationic polymers with DNA could be pegylated through a supramolecular process using inclusion complexation between the CD moieties and a modified PEO. Finally, new cationic polyrotaxanes composed of multiple oligoethylenimine-grafted CDs threaded and end-capped on a block copolymer chain were designed and synthesized as a new class of polymeric gene delivery vectors, where the chain-interlocked cationic cyclic units formed an integrated supramolecular entity to function as a macromolecular gene vector. The development of the supramolecular biomaterials through inclusion complexation has opened up a new approach for designing novel drug and gene delivery systems, which may have many advantages over the systems based on the conventional polymeric materials.